Prion diseases are neurodegenerative disorders characterized by rapid cognitive and motor decline. Similar to amyloid-? in Alzheimer?s disease, certain prion aggregates spread through the brain and accumulate as parenchymal and vascular plaques. We hypothesize that prions, similar to amyloid-?, can transit through the interstitial fluid for clearance in perivascular channels. We recently found that shortening heparan sulfate chain length in mice reduced parenchymal prion plaques yet increased vascular plaques in the brain, consistent with improved prion clearance through the interstitial fluid (ISF). Survival time was also prolonged. We and others also recently found that the water transport protein, aquaporin 4, redistributes from astrocyte end feet in prion-affected blood vessels, indicating alterated perivascular channels in prion disease. In addition, aquaporin 4 expression is elevated in prion disease. In Aim 1, we will define when and how vascular channels and the blood brain barrier are modified during prion disease in humans and mice. In Aim 2, we will employ genetic mouse models with impaired CSF-ISF exchange to determine how impairing fluid exchange impacts prion disease progression and phenotype. We will also establish the prion conformers that most severely modify water channel transport proteins, CSF-ISF fluid exchange, and the blood brain barrier in humans and in mice.